Mechanisms of pulmonary involvement

Respiratory involvement can occur in nearly all of the rheumatological disorders affecting children, and the reasons for this are multifactorial. Lung structures are highly vascular and are exposed to external stimuli, organisms and toxins, making it particularly susceptible to inflammation. Macrophages ingest and degrade these inhaled antigenic stimuli and serve as antigenic presenting cells, leading to inappropriate activation of autoreactive CD4 T-lymphocyte and B-lymphocyte. This mechanism is responsible for pathogenic autoantibodies. The underlying autoimmune process determines the part of the respiratory system that will be predominately affected. Since pleura shares structures and function akin to joint synovia, it is often the commonest site for inflammation to occur. Acute expression with resolution sometimes occurs, but chronic and relapsing scenarios are more common.2

Juvenile systemic lupus erythematosus

JSLE is an autoimmune disease, characterised by the presence of a wide variety of autoantibodies resulting in multisystem inflammation and organ damage. There is significant female dominance in the postpubertal age group, which is less pronounced in younger age groups. It presents before the age of 18 in between 15% and 20% of individuals,3 with pulmonary involvement occurring in up to 40% within the first year of diagnosis, doubling that at any point in the disease course.4 The associated respiratory complications in JSLE can be categorised into acute and chronic (see table 1).

Granulomatosis with polyangitis

GPA (formerly called ‘Wegener's granulomatosis’) is an immune-mediated necrotising granulomatous vasculitis, of unknown aetiology, characterised by anti-neutrophil cytoplasmic antibodies (ANCA) directed against proteinase 3 (PR3). It is rare in children, with its peak incidence in adults in their fourth to sixth decade.1 However, it is the most common ANCA-associated vasculitis occurring in childhood.24 It usually manifests in the triad of symptoms affecting the upper airways, lower airways and kidneys. Children often present insidiously with sinus pain, dyspnoea and cough, haemoptysis, arthritis or joint pain and skin rashes or ulceration.25 ,26 Accompanied symptoms of stridor or hoarseness may be indicative of subglottic stenosis, which may occur more frequently in childhood-onset GPA than adults. Upper airway signs also include rhinorrhoea, purulent or bloody discharge, persistent otitis media with hearing loss, sinusitis, proptosis caused by extraocular pseudotumour and saddle-nose deformity.25 ,26

Pulmonary disease complicates nearly 75% of childhood cases of GPA,27 with symptoms of pleuritic pain, cough, stridor, dyspnoea and haemoptysis predominating.25 Similar to subglottic stenosis, around one-third of these patients may have stenosis in the tracheobronchial tree.28 Haemoptysis in these patients may suggest AH. About half of all children with GPA will have abnormalities seen on CXR, which are usually pulmonary nodules, cavities or fixed infiltrates.26 ,29 Figure 1 shows a teenage girl who was found to have a fluid-filled cavitating nodule on radiological imaging. Other findings may be pneumothoraces, mediastinal lymphadenopathy and pleural effusions.1 CXR changes may easily be confused with infective changes, which are also a common cause of morbidity and mortality in GPA.26

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Figure 1

A fluid-filled cavitating nodule on radiological imaging in a young girl with granulomatosis with polyangitis.

Diagnosis of GPA can be made by a combination of histology, serology or clinical findings. Lung biopsy is rarely required due to the presence of skin, renal or upper airway lesions, allowing an easier and safer biopsy procedure. Serum ANCA directed at PR3 is found in 70–90% of patients with active disease and is one of the six classification criteria.24 PFTs are abnormal in up to 50% of cases, showing a mixture of obstructive and restrictive defects. Patients with laryngotracheobronchial disease often need bronchoscopy or CT scan for diagnosis. Infections may mask symptoms and account for a high level of mortality, so must be considered in all patients with known GPA and a respiratory deterioration. Treatment is usually with high-dose corticosteroids combined with any one or combination of immunosuppressive agents (such as cyclophosphamide, azathioprine, methotrexate (MTX), mycophenolate mofetil or rituximab) with an aim to achieve complete remission.24

Juvenile dermatomyositis

JDM is an inflammatory myopathy of unknown aetiology, which leads to multisystem disease. Although it is rare, it is still the commonest inflammatory myopathy of childhood. Classically, it is characterised by proximal muscle weakness, a rash and raised serum skeletal muscle enzymes. Pulmonary involvement can be subdivided into three distinct entities30:

• A complication of neuromuscular weakness (eg, hypoventilation, aspiration pneumonia)

• ILD

• A complication of immunosuppressive drug therapy (as discussed later)

ILD is a frequent pulmonary complication in adults with myositis, occurring in between 30% and 50% of individuals,31 ,32 where respiratory signs prove a poor indicator for prognosis. Instead, a strong predictive factor for ILD is the presence of circulating antihistidyl transfer RNA synthetase antibodies known as anti-Jo-1.33 This pattern of ILD occurs rarely in children, but has a poor prognosis with a 5-year survival of only 70%.34 Typically, ILD presents with increasing cough and progressive dyspnoea, although it may be asymptomatic.

Early asymptomatic lung disease can be detected by the use of PFTs in this group of children. Similarly to adult studies, restrictive lung disorders are seen most frequently,32 although obstructive patterns are also seen.35 PFTs can reveal asymptomatic lung disease in around half of patients;34 ,35 interestingly, these changes are noticed at the onset of the disease as well as during follow-up. DLCO may also be low in almost half of patients,36 although this is not specific for ILD as it can occur secondary to pulmonary hypertension, which may occur in those with a variety of connective tissue diseases. HRCT is the best imaging modality to assess for signs of early ILD in adults. However, due to the disease rarity in children, a lung biopsy may still be required to confirm the diagnosis.1 In a case–control study of 59 patients with JDM,36 37% patients were found to have abnormalities on HRCT, with ILD (14%), chest wall calcinosis (14%) and airways disease (15%). They also found associated restrictive patterns on PFTs in 26% of the study population, demonstrating that HRCT is superior at diagnosing pulmonary complications.

Juvenile idiopathic arthritis

JIA is the most common rheumatological condition of childhood, occurring in up to 150 per 100 000 children.37 It is a heterogeneous group of diseases characterised by an arthritis that begins before the age of 16 years, persisting for at least six weeks, and for which no specific cause can be found. The International League of Associations for Rheumatology classification of JIA divided the condition into the seven subtypes: systemic, oligoarticular, polyarticular RF negative, polyarticular RF positive, enthesitis-related, psoriatic and unclassified.38

Pulmonary disease is a well-described complication of rheumatoid arthritis, leading to significant morbidity and mortality. Pulmonary complications in JIA are rare with an estimated prevalence of 4–8%.39 Radiological abnormalities include pleural effusion, pneumonitis, and interstitial reticular and nodular infiltrates. The most severe pulmonary consequences have been seen with the systemic and polyarticular subtypes of JIA.1

The commonest respiratory presentation occurs in systemic JIA (sJIA) in the form of pleuritis with or without pericarditis as a part of serositis. There is an increasing frequency of the rarer and more serious pulmonary complications associated with sJIA. These are pulmonary artery hypertension, ILD and alveolar proteinosis. These are all processes that are likely to be the result of severe uncontrolled systemic disease activity and have a high morbidity. It is unclear why reported cases of these conditions have increased over recent years, but the rising incidence may be linked to the widespread introduction of biologics, although this remains controversial.40 ,41

The use of PFTs for the diagnosis and monitoring of JIA is crucial. Studies have shown that PFT abnormalities occur in more than half of all children with JIA, with restrictive patterns seen most frequently.42 DLCO reductions are more variably reported as occurring in up to 45% of patients.1 ,2 ,42 There is a significant inverse correlation between lung function parameters and the rheumatoid factor titre, erythrocyte sedimentation rate, disease duration and duration of MTX use.42

As well as plain film X-rays and PFTs, HRCT may be better able to detect ILD at an earlier stage, and thus potentially improve the long-term prognosis. BAL may also aid in diagnosis of ILD in such cases by allowing the analysis of inflammatory cells and excluding infectious processes. However, lung biopsy is still the gold standard for assessing pleuropulmonary disease in JIA and should be considered when it is necessary to distinguish between an inflammatory, vasculitic or infectious process prior to starting therapy.2 Most patients with pulmonary disease proven by biopsy are rheumatoid factor positive. The mainstay of treatment for JIA is NSAIDs and intra-articular corticosteroids. However, many children require second-line MTX, or even biological agents, which as discussed later are implicated in lung injury.

Scleroderma/systemic sclerosis

SSc is rare in children, occurring in an estimated 0.05 per 100 000 children,43 although an estimated 10% of adults have the onset of their disease in childhood.44 It is a connective tissue disease characterised by tightening and sclerosis of the skin. It occurs in two forms: ‘limited’ and ‘diffuse’. The diffuse form occurs more frequently in children, in approximately 90% of cases,45 involving multiple organ systems that may overlap with other connective tissue disorders. SSc is an autoimmune vasculopathy characterised by significant endothelial damage, mediated by cytokines such as endothelin-1. Pulmonary involvement in SSc is considered common enough (around 50%) to be included as one of the minor diagnostic criteria, although patients are often asymptomatic. The two major forms of lung involvement are ILD (which is most common46) and pulmonary hypertension. Symptoms of ILD such as dyspnoea and cough, and radiographic changes such as groundglass opacities and reticular patterns are only found in 10–25% of children. HRCT and PFTs (demonstrating a reduced DLCO) are more sensitive in detecting early asymptomatic ILD, and thus serial PFTs are the best way to monitor for lung disease in SSc.

Mixed connective tissue disease

MCTD was first described as a distinct rheumatological condition in 1972.47 It is characterised by the presence of features from a variety of autoimmune conditions (primarily JSLE, scleroderma and dermatomyositis) as well as detectable serum anti-RNP autoantibodies. It is rare in children, accounting for only 0.1–0.5% of paediatric rheumatology cases.48 To diagnose MCTD, the following three criteria must be met49:

1. Raynaud's phenomenon

2. detectable anti-RNP antibodies

3. one abnormal sign/symptom from either JSLE, SSc or dermatomyositis

Presentation often occurs slowly over time, with some patients being labelled as having ‘undifferentiated connective tissue disease’ before meeting the diagnostic criteria.1 Pulmonary involvement develops in up to 75% of adult patients with MCTD,50 and although the exact prevalence in children is unknown, it is thought to be similar. The main respiratory complications are pleural effusions, pulmonary fibrosis and pulmonary hypertension. Patients with MCTD are less likely to develop severe renal or central nervous system involvement compared with JSLE, so it is, therefore, felt to have a better prognosis than those conditions. However, if pulmonary complications develop, they cause a significant increase in mortality, especially if complicated by pulmonary hypertension (which is less common in children than in adults).1 The clinical course can be variable, so treatment is specific to the complications encountered, and the conventional therapies used for JSLE, SSc and JDM are effective.

Sarcoidosis

Sarcoidosis is a chronic inflammatory multisystem disease of unknown aetiology that rarely affects children. It is characterised by epithelioid cell granulomatous lesions that are non-caseating (which therefore differ from those in GPA) and can develop in many different organs, predominately the lung. There are two distinct presentations in children. The first is known as early-onset sarcoidosis and has a favourable prognosis. It occurs at the age of ≤4 years of age and has a triad of skin rash, uveitis and arthritis. It is thought to be a sporadic form of Blau's syndrome. It rarely presents with respiratory complications.1 ,2

In children >8 years of age, the classical sarcoidosis, which presents similarly in adults, tends to predominate. Granulomas can occur in any organ, but are most common in the lungs, lymph nodes, eyes skin and liver.1 Pulmonary involvement can occur in up to 100% with evidence of abnormalities on CXRs, which may even precede clinical symptoms.51–53 The pulmonary lymph nodes and pulmonary parenchyma are most commonly affected. Common symptoms of respiratory involvement are exertional dyspnoea, chest pain, cough and wheeze, although many may be asymptomatic. Radiographic changes are divided into the categories seen in table 2, with the majority of children presenting with stage I disease (61–71%).51 ,54 PFTs may be normal in stage 0 or stage I disease, but a restrictive pattern with decreased DLCO is the most common abnormality.54

Progression of granulomatous lung lesions to pulmonary fibrosis (stage IV) and thus end-stage lung disease is a fatal complication of sarcoidosis. Other serious complications include the development of bronchiectasis or chronic infections. Such concerning infections include the development of an aspergilloma in damaged tissue, which may present with haemoptysis. In some patients, lung disease spontaneously resolves within two years. Treatment is considered for those with lung disease in the higher stages, where corticosteroids are first line, followed by MTX and hydroxychloroquine.1

Drug-induced pulmonary complications

A variety of drugs are used for rheumatological conditions that may themselves produce respiratory side effects. There is an obvious link between immunosuppressant therapy and the acquisition of opportunistic infections. MTX is an immunosuppressive drug used commonly in JIA and other rheumatological conditions in children. Pulmonary toxicity is a well-established side effect of MTX treatment and manifests in a variety of presentations, the most common being hypersensitivity pneumonitis, with an incidence between 1% and 2%.55 It is more prevalent in the adult population and typically presents with dry cough, fever and dyspnoea, and can be hard to differentiate from an infective process. CXRs may reveal interstitial or alveolar infiltrates, although routine PFTs and HRCTs have not been shown to be useful when monitoring at-risk patients for toxicity.55 MTX should be discontinued and high-dose corticosteroids may be required. Other pulmonary manifestations of MTX toxicity include pulmonary fibrosis, organising pneumonia, acute lung injury and reactive airways disease.2

With the newer biological agents used in rheumatological conditions, infection remains the commonest respiratory complication. Such infections are usually opportunistic, although the tumour necrosis factor-α inhibitors increase the risk of the reactivation of latent tuberculosis.2 Thus, it is imperative to screen for latent tuberculosis prior to the commencement of such therapies.55 There is evidence of rituximab leading to the development of ILD in adults,56 presenting with dyspnoea, tachypnoea, fever and hypoxaemia. HRCT and PFTs help to establish the diagnosis. Unsurprisingly with this agent's increasing spectrum of use for different pathologies, there is a case report of this complication affecting a paediatric patient.57

Other drugs often used in rheumatological conditions may cause a clinical picture of interstitial pneumonitis (see table 3). A failure to recognise pulmonary toxicity of drugs may lead to their continuation and thus compound the destructive process. This is important in conditions where pulmonary complications of the disease itself are well known and where drug-induced pulmonary toxicity may not be the initial concern.

The role of respiratory monitoring

As outlined in the descriptions above, respiratory involvement can occur in the majority of rheumatological conditions affecting children and may be even asymptomatic. Therefore, there is a role for the regular pulmonary function screening tests to be undertaken at regular intervals to observe for any decline, so that targeted interventions can happen early. We suggest that outpatient reviews should be held jointly between paediatric rheumatologists and respiratory physicians, working together to monitor for early pulmonary involvement. These clinics offer an opportunity to undertake extensive lung function testing, and consideration of further investigations such as HRCT and DLCO. This is also an opportune time to discuss lifestyle measures such as smoking avoidance. This model has allowed us to pickup pulmonary involvement in these patients early, even if many of them are asymptomatic.

This partnership allows for ad hoc reviews of patients presenting acutely with respiratory symptoms such as cough, dyspnoea, chest tightness or sleep disturbance. It is, however, crucial that any paediatrician who may encounter a child with a rheumatological condition presenting either acutely or insidiously is aware of the respiratory complications outlined in this article. The awareness and prompt investigation and treatment of the pulmonary manifestations of these rheumatological conditions may be the key factor in determining prognosis.